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Special Issue "Novel Aspects in Kidney Disease in Diabetes"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (28 February 2021).

Special Issue Editors

Prof. Dr. Giuseppina T. Russo
E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine, Policlinico Universitario “G. Martino”, Via Consolare Valeria, 98124 Messina, Italy
Interests: diabetes; diabetic kidney disease; gender medicine; macrovascular disease; lipid metabolism; homocysteine; genetics
Special Issues and Collections in MDPI journals
Prof. Dr. Domenico Santoro
E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
Interests: renal disease; glomerulonephritis; hemodialysis; renin angiotensin system
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Diabetes mellitus (DM) affects millions of people worldwide, and ~40% of them may have diabetic nephropathy.

We are witnessing a dramatic change in the pathophysiology, management and therapeutic approach of diabetic nephropathy, now termed kidney disease associated with DM. Accumulating evidence has recently been focused on clarifying the different morphological and pathophysiological aspects of renal lesions associated with diabetes, especially the non-albuminuric phenotype. There is still an ongoing debate on the prevalence and the role of different forms of kidney disease in diabetic subjects, other than diabetic kidney disease and the potential biomarkers able to distinguish among them, when the biopsy is not feasible. Renewed hope comes from the recent evidences from experimental research, and from cardiovascular outcomes trials (CVOTs), which have demonstrated the benefits of the new classes of hypoglycemic drugs on the occurrence and progression of kidney disease as well as on cardiovascular disease (CVD) risk. Finally, the high CVD risk in DM subjects with kidney disease calls for the urgent need to translate basic research into clinical practice, in order to help people with DM to survive longer and without the specter of dialysis in front of them.

This Special Issue will deal with several aspects of diabetes and its renal complications, as specified below. We welcome original research articles, comprehensive reviews and short communications with a focus on molecular level studies.

Potential topics include, but are not limited to, the relationship between kidney disease associated with diabetes with:

1. Sex/gender differences;

2. Renal morphology changes in diabetic patients;

3. Differences between Type 1 and type 2 diabetes;

4. Role of genetics/omics

5. Predictive models/artificial intelligence;

6. New biomarkers/new applications of old biomarkers;

7. Phenotyping DKD: isolated low eGFR vs. albuminuria;

8. New approaches with albuminuria: overcoming traditional cut-offs;

9. Role of the renin–angiotensin system and SGT2i;

10. Predictors of fast progression in patients with diabetes mellitus and renal failure;

11. Role of vitamin D status in diabetic patients with renal disease;

12. Management of Diabetic Mellitus in patients with reduced renal function;

13. Oxidative stress/endothelial dysfunction/inflammation and the progression of diabetic nephropathy;

14. Potential beneficial effects of SGTL2 inhibitors and GLP1-RAs and/or their combination;

15. Mineral corticoid receptor antagonist and diabetes mellitus;

16. Ageing, kidney and diabetes management;

17. Cardiovascular risk factors and diabetic kidney;

18. Nutritional aspects in diabetic patients with chronic renal failure.

Prof. Dr. Giuseppina T. Russo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • diabetic kidney disease
  • microalbuminuria
  • gender
  • genetics, omics, artificial intelligence, biomarkers
  • low protein diet in diabetic nephropathy
  • ageing
  • sglt2
  • glp1-ras

Related Special Issue

Published Papers (10 papers)

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Research

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Article
A Computational Model of Kidney Function in a Patient with Diabetes
Int. J. Mol. Sci. 2021, 22(11), 5819; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115819 - 29 May 2021
Cited by 1 | Viewed by 821
Abstract
At the onset of diabetes, the kidney grows large and the glomerular filtration rate becomes abnormally high. These structural and hemodynamics changes affect kidney function and may contribute to the development of chronic kidney disease. The goal of this study is to analyze [...] Read more.
At the onset of diabetes, the kidney grows large and the glomerular filtration rate becomes abnormally high. These structural and hemodynamics changes affect kidney function and may contribute to the development of chronic kidney disease. The goal of this study is to analyze how kidney function is altered in patients with diabetes and the renal effects of an anti-hyperglyceamic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish that goal, we have developed a computational model of kidney function in a patient with diabetes and conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Simulation results indicate that diabetes-induced hyperfiltration and tubular hypertrophy enhances Na+ transport, especially along the proximal tubules and thick ascending limbs. These simulations suggest that SGLT2 inhibition may attenuate glomerular hyperfiltration by limiting Na+-glucose transport, raising luminal [Cl] at the macula densa, restoring the tubuloglomerular feedback signal, thereby reducing single-nephron glomerular filtration rate. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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Article
Effects of Environmental Conditions on Nephron Number: Modeling Maternal Disease and Epigenetic Regulation in Renal Development
Int. J. Mol. Sci. 2021, 22(8), 4157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084157 - 16 Apr 2021
Viewed by 753
Abstract
A growing body of evidence suggests that low nephron numbers at birth can increase the risk of chronic kidney disease or hypertension later in life. Environmental stressors, such as maternal malnutrition, medication and smoking, can influence renal size at birth. Using metanephric organ [...] Read more.
A growing body of evidence suggests that low nephron numbers at birth can increase the risk of chronic kidney disease or hypertension later in life. Environmental stressors, such as maternal malnutrition, medication and smoking, can influence renal size at birth. Using metanephric organ cultures to model single-variable environmental conditions, models of maternal disease were evaluated for patterns of developmental impairment. While hyperthermia had limited effects on renal development, fetal iron deficiency was associated with severe impairment of renal growth and nephrogenesis with an all-proximal phenotype. Culturing kidney explants under high glucose conditions led to cellular and transcriptomic changes resembling human diabetic nephropathy. Short-term high glucose culture conditions were sufficient for long-term alterations in DNA methylation-associated epigenetic memory. Finally, the role of epigenetic modifiers in renal development was tested using a small compound library. Among the selected epigenetic inhibitors, various compounds elicited an effect on renal growth, such as HDAC (entinostat, TH39), histone demethylase (deferasirox, deferoxamine) and histone methyltransferase (cyproheptadine) inhibitors. Thus, metanephric organ cultures provide a valuable system for studying metabolic conditions and a tool for screening for epigenetic modifiers in renal development. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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Article
TP63 Is Significantly Upregulated in Diabetic Kidney
Int. J. Mol. Sci. 2021, 22(8), 4070; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084070 - 15 Apr 2021
Viewed by 615
Abstract
The role of tumor protein 63 (TP63) in regulating insulin receptor substrate 1 (IRS-1) and other downstream signal proteins in diabetes has not been characterized. RNAs extracted from kidneys of diabetic mice (db/db) were sequenced to identify genes that are involved in kidney [...] Read more.
The role of tumor protein 63 (TP63) in regulating insulin receptor substrate 1 (IRS-1) and other downstream signal proteins in diabetes has not been characterized. RNAs extracted from kidneys of diabetic mice (db/db) were sequenced to identify genes that are involved in kidney complications. RNA sequence analysis showed more than 4- to 6-fold increases in TP63 expression in the diabetic mice’s kidneys, compared to wild-type mice at age 10 and 12 months old. In addition, the kidneys from diabetic mice showed significant increases in TP63 mRNA and protein expression compared to WT mice. Mouse proximal tubular cells exposed to high glucose (HG) for 48 h showed significant decreases in IRS-1 expression and increases in TP63, compared to cells grown in normal glucose (NG). When TP63 was downregulated by siRNA, significant increases in IRS-1 and activation of AMP-activated protein kinase (AMPK (p-AMPK-Th172)) occurred under NG and HG conditions. Moreover, activation of AMPK by pretreating the cells with AICAR resulted in significant downregulation of TP63 and increased IRS-1 expression. Ad-cDNA-mediated over-expression of tuberin resulted in significantly decreased TP63 levels and upregulation of IRS-1 expression. Furthermore, TP63 knockdown resulted in increased glucose uptake, whereas IRS-1 knockdown resulted in a decrease in the glucose uptake. Altogether, animal and cell culture data showed a potential role of TP63 as a new candidate gene involved in regulating IRS-1 that may be used as a new therapeutic target to prevent kidney complications in diabetes. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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Article
The Effect of Far-Infrared Therapy on the Peritoneal Expression of Glucose Degradation Products in Diabetic Patients on Peritoneal Dialysis
Int. J. Mol. Sci. 2021, 22(7), 3732; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073732 - 02 Apr 2021
Cited by 1 | Viewed by 644
Abstract
Peritoneal dialysis (PD) is a treatment modality for end-stage renal disease (ESRD) patients. Dextrose is a common osmotic agent used in PD solutions and its absorption may exacerbate diabetes mellitus, a common complication of ESRD. PD solutions also contain glucose degradation products (GDPs) [...] Read more.
Peritoneal dialysis (PD) is a treatment modality for end-stage renal disease (ESRD) patients. Dextrose is a common osmotic agent used in PD solutions and its absorption may exacerbate diabetes mellitus, a common complication of ESRD. PD solutions also contain glucose degradation products (GDPs) that may lead to encapsulating peritoneal sclerosis (EPS), a severe complication of PD. A previous study showed that far-infrared (FIR) therapy improved a patient’s gastrointestinal symptoms due to EPS. Due to limited literature on the matter, this study aims to investigate dialysate GDPs and peritoneal function in diabetic patients on PD. Thirty-one PD patients were enrolled and underwent 40 min of FIR therapy twice daily for six months. We demonstrated the effect of FIR therapy on the following: (1) decrease of methylglyoxal (p = 0.02), furfural (p = 0.005), and 5-hydroxymethylfurfural (p = 0.03), (2) increase of D/D0 glucose ratio (p = 0.03), and (3) decrease of potassium levels (p = 0.008) in both DM and non-DM patients, as well as (4) maintenance and increase of peritoneal Kt/V in DM and non-DM patients, respectively (p = 0.03). FIR therapy is a non-invasive intervention that can decrease dialysate GDPs in PD patients by improving peritoneal transport rate and solute removal clearance, while also maintaining dialysis adequacy. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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Article
CD28null and Regulatory T Cells Are Substantially Disrupted in Patients with End-Stage Renal Disease Due to Diabetes Mellitus
Int. J. Mol. Sci. 2021, 22(6), 2975; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062975 - 15 Mar 2021
Viewed by 555
Abstract
Background: End-stage renal disease (ESRD) is associated with alterations in T-cell immunity, including increased CD28null and reduced regulatory T cells (Tregs). However, whether immune disturbances are due to ESRD or primary disease is not yet clear. As diabetes mellitus is the leading cause [...] Read more.
Background: End-stage renal disease (ESRD) is associated with alterations in T-cell immunity, including increased CD28null and reduced regulatory T cells (Tregs). However, whether immune disturbances are due to ESRD or primary disease is not yet clear. As diabetes mellitus is the leading cause of ESRD, we evaluated its impact on the immune profile of ESRD patients. Methods: CD28null, Tregs, and natural killer cells were initially analyzed by flow cytometry in 30 predialysis ESRD patients due to diabetes (DM), 30 non-DM (NDM), and 25 healthy controls. Measurements were repeated after 6 months on hemodialysis (HD) or peritoneal dialysis (CAPD). Results: The percentage of CD4 + CD28null cells, CD8 + CD28null cells, and Tregs showed significant differences in DM, NDM, and controls; mean rank 33.71 vs. 25.68 vs. 18.88, p = 0.006, 37.79 vs. 28.82 vs. 17.08, p = 0.008, and 20.79 vs. 26.12 vs. 41.33, p = 0.001, respectively. DM vs. NDM had increased CD4 + CD28null and CD8 + CD28null cells, 11.5% (1.5%–24%) vs. 4.1% (0–42.3%), p = 0.02 and 61.3% (24%–76%) vs. 43% (5.7%–85%), p = 0.04, respectively. After 6 months on HD but not CAPD, DM showed a significant further increase in CD4 + CD28null cells, from 30 (14–100) to 52.7 (15–203), p = 0.02; and CD8 + CD28null cells, from 137 (56–275) to 266 (103–456), p = 0.01. Conclusions: Diabetes mellitus affects T-cell subtypes even at predialysis stage, though changes become more prominent after commencement on HD. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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Review

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Review
TGF-Beta as a Master Regulator of Diabetic Nephropathy
Int. J. Mol. Sci. 2021, 22(15), 7881; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157881 - 23 Jul 2021
Viewed by 675
Abstract
Diabetic nephropathy (DN) is one of the most common complications in diabetes mellitus and the leading cause of end-stage renal disease. TGF-β is a pleiotropic cytokine and has been recognized as a key mediator of DN. However, anti-TGF-β treatment for DN remains controversial [...] Read more.
Diabetic nephropathy (DN) is one of the most common complications in diabetes mellitus and the leading cause of end-stage renal disease. TGF-β is a pleiotropic cytokine and has been recognized as a key mediator of DN. However, anti-TGF-β treatment for DN remains controversial due to the diverse role of TGF-β1 in DN. Thus, understanding the regulatory role and mechanisms of TGF-β in the pathogenesis of DN is the initial step towards the development of anti-TGF-β treatment for DN. In this review, we first discuss the diverse roles and signaling mechanisms of TGF-β in DN by focusing on the latent versus active TGF-β1, the TGF-β receptors, and the downstream individual Smad signaling molecules including Smad2, Smad3, Smad4, and Smad7. Then, we dissect the regulatory mechanisms of TGF-β/Smad signaling in the development of DN by emphasizing Smad-dependent non-coding RNAs including microRNAs and long-non-coding RNAs. Finally, the potential therapeutic strategies for DN by targeting TGF-β signaling with various therapeutic approaches are discussed. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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Review
Gender Differences in Diabetic Kidney Disease: Focus on Hormonal, Genetic and Clinical Factors
Int. J. Mol. Sci. 2021, 22(11), 5808; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115808 - 28 May 2021
Cited by 2 | Viewed by 1274
Abstract
Diabetic kidney disease (DKD) is one of the most serious complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- [...] Read more.
Diabetic kidney disease (DKD) is one of the most serious complications of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM). Current guidelines recommend a personalized approach in order to reduce the burden of DM and its complications. Recognizing sex and gender- differences in medicine is considered one of the first steps toward personalized medicine, but the gender issue in DM has been scarcely explored so far. Gender differences have been reported in the incidence and the prevalence of DKD, in its phenotypes and clinical manifestations, as well as in several risk factors, with a different impact in the two genders. Hormonal factors, especially estrogen loss, play a significant role in explaining these differences. Additionally, the impact of sex chromosomes as well as the influence of gene–sex interactions with several susceptibility genes for DKD have been investigated. In spite of the increasing evidence that sex and gender should be included in the evaluation of DKD, several open issues remain uncovered, including the potentially different effects of newly recommended drugs, such as SGLT2i and GLP1Ras. This narrative review explored current evidence on sex/gender differences in DKD, taking into account hormonal, genetic and clinical factors. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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Review
Kidney Biopsy in Type 2 Diabetic Patients: Critical Reflections on Present Indications and Diagnostic Alternatives
Int. J. Mol. Sci. 2021, 22(11), 5425; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115425 - 21 May 2021
Cited by 1 | Viewed by 786
Abstract
Roughly 3% of patients worldwide with a new diagnosis of type 2 diabetes mellitus (T2DM) already have an overt nephropathy at diagnosis and about 20–30% of the remaining ones develop a complication of this kind later in life. The early identification of kidney [...] Read more.
Roughly 3% of patients worldwide with a new diagnosis of type 2 diabetes mellitus (T2DM) already have an overt nephropathy at diagnosis and about 20–30% of the remaining ones develop a complication of this kind later in life. The early identification of kidney disease in diabetic patients is important as it slows its progression, which is important not only because this reduces the need for renal replacement therapy, but also because it decreases the high rate of mortality and morbidity associated with a reduction in kidney function. The increasing prevalence of type 2 diabetes and the consequent greater probability of finding different types of kidney diseases in diabetic patients frequently gives rise to overlapping diagnoses, a definition encompassing the differential diagnosis between diabetic and non-diabetic kidney disease. The issue is made more complex by the acknowledgement of the increasing frequency of presentations of what is termed “diabetic kidney disease” without relevant proteinuria, in particular in T2DM patients. Distinguishing between diabetes related and non-diabetes related forms of kidney disease in diabetic patients is not only a semantic question, as different diseases require different clinical management. However, while the urologic and macrovascular complications of diabetes, as well as overlapping parenchymal damage, can be diagnosed by means of imaging studies, often only a kidney biopsy will make a differential diagnosis possible. In fact, the coexistence of typical diabetic lesions, such as nodular glomerulopathy or glomerulosclerosis, with different glomerular, vascular and tubulo-interstitial alterations has been extensively described, and an analysis of the dominant histological pattern can contribute to determining what therapeutic approach should be adopted. However, due to the high frequency of kidney diseases, and to the fact that T2DM patients are often affected by multiple comorbidities, a kidney biopsy is not generally performed in T2DM patients. What follows is a review aiming to discuss the diagnostic work-up, on the base of clinical, laboratory and imaging criteria, and evaluate the present indications and alternatives to renal biopsy. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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Review
Kidney Disease in Diabetic Patients: From Pathophysiology to Pharmacological Aspects with a Focus on Therapeutic Inertia
Int. J. Mol. Sci. 2021, 22(9), 4824; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094824 - 01 May 2021
Cited by 3 | Viewed by 1140
Abstract
Diabetes mellitus represents a growing concern, both for public economy and global health. In fact, it can lead to insidious macrovascular and microvascular complications, impacting negatively on patients’ quality of life. Diabetic patients often present diabetic kidney disease (DKD), a burdensome complication that [...] Read more.
Diabetes mellitus represents a growing concern, both for public economy and global health. In fact, it can lead to insidious macrovascular and microvascular complications, impacting negatively on patients’ quality of life. Diabetic patients often present diabetic kidney disease (DKD), a burdensome complication that can be silent for years. The average time of onset of kidney impairment in diabetic patients is about 7–10 years. The clinical impact of DKD is dangerous not only for the risk of progression to end-stage renal disease and therefore to renal replacement therapies, but also because of the associated increase in cardiovascular events. An early recognition of risk factors for DKD progression can be decisive in decreasing morbidity and mortality. DKD presents patient-related, clinician-related, and system-related issues. All these problems are translated into therapeutic inertia, which is defined as the failure to initiate or intensify therapy on time according to evidence-based clinical guidelines. Therapeutic inertia can be resolved by a multidisciplinary pool of healthcare experts. The timing of intensification of treatment, the transition to the best therapy, and dietetic strategies must be provided by a multidisciplinary team, driving the patients to the glycemic target and delaying or overcoming DKD-related complications. A timely nephrological evaluation can also guarantee adequate information to choose the right renal replacement therapy at the right time in case of renal impairment progression. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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Review
SGLT2is and Renal Protection: From Biological Mechanisms to Real-World Clinical Benefits
Int. J. Mol. Sci. 2021, 22(9), 4441; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094441 - 23 Apr 2021
Cited by 1 | Viewed by 761
Abstract
In recent years, following the publication of results from several RCTs, first on cardiovascular and more recently on renal outcomes, SGLT2is have become the standard of care to prevent diabetic kidney disease and slow its progression. This narrative review focuses on biological mechanisms, [...] Read more.
In recent years, following the publication of results from several RCTs, first on cardiovascular and more recently on renal outcomes, SGLT2is have become the standard of care to prevent diabetic kidney disease and slow its progression. This narrative review focuses on biological mechanisms, both renal and extrarenal, underlying kidney protection with SGLT2is. Furthermore, data from cardiovascular as well as renal outcome trials, mostly conducted in diabetic patients, are presented and discussed to provide an overview of current uses as well as the future therapeutic potential of these drugs. Full article
(This article belongs to the Special Issue Novel Aspects in Kidney Disease in Diabetes)
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